Teclistamab salvage therapy for multiple myeloma relapse after allogeneic hemopoietic stem cell transplant: A case report
Authors: Francesco Zaja, Elisa Lucchini, Monica Poiani, Eugenio Sbisà, Sara Mohamed, Eleonora De Bellis, Manuela Caizzi, Clara Palmieri, Stefano Loiacono, Marilena Granzotto, Francesca Sirianni, Giovanni De Sabbata
Journal: American Journal of Hematology (2023)

Treatment of relapse/refractory (R/R) multiple myeloma (MM) is becoming challenging; the prognosis of patients previously exposed to three or more classes of drugs and active disease is dismal with a median survival of 9 months or less.1 According to the ASCO/CCO guidelines,2 allogeneic hemopoietic stem cell transplant (HSCT) can be considered a possible salvage therapy in selected high-risk young MM patients with a suitable donor. In recent years, several new immune therapeutic agents, drug-conjugated antibodies, bispecific antibodies, and CAR-T cells have shown remarkable therapeutic activity in R/R MM patients, representing important therapeutic opportunities. Bispecific antibodies (BAs) are a novel class of monoclonal antibodies with dual affinity versus T-cells and tumor-specific antigens that have been generated to enhance immune cellular response against neoplastic cells. Teclistamab (Te) is a BA that targets CD3 and the B-cell maturation antigen (BCMA) expressed on myeloma cells: once administered, Te engages CD3-positive T-cells promoting their redirection and activation against BCMA-positive cells, favoring MM cells lysis.3 In MajesTEC-1 phase 1–2 study, Te was administered in 165 patients with R/R MM who previously received at least three lines of therapy, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. The results of this study showed an overall response rate and complete response rate of 63% and 39.4%, respectively. The median time to initial and best response was 1.2 months (range, 0.2–5.5) and 3.8 months (range, 1.1–16.8), and the median duration of response and progression-free survival (PFS) was 18.4 months (95% confidence interval [CI], 14.9 to not estimable) and 11.3 months (95% CI, 8.8–17.1), respectively.4 To our knowledge, there are currently no available data regarding the use of Te in patients with MM relapsed after HSCT. The administration of Te in this setting, especially in patients who achieve full lymphocyte chimerism and are not receiving further anti-MM treatments, may have several implications related to the status of T-cell fitness, the impact on anti-tumor cell activity, and the potential development of graft versus host disease (GVHD). We herein report the case of a young patient with multi-refractory MM who relapsed after HSCT and was treated with Te single agent achieving stable deep stringent complete response (SCR) with no occurrence of GVHD. Our patient was diagnosed in August 2017, at 44 years old, with micromolecular K MM, R-ISS 2 with t(11;14). He initially presented with acute renal failure and hypercalcemia. He received initial induction therapy with bortezomib, thalidomide, and dexamethasone (VTD) with no response. He was then treated with dexamethasone, cyclophosphamide, etoposide, and cisplatin (D-CEP) for two cycles, cyclophosphamide and stem cell harvest followed by two autologous stem cell transplant achieving partial response according to International Myeloma Working Group consensus criteria for response and minimal residual disease assessment. Lenalidomide maintenance was started in December 2018, 2 months after the second transplant. In February 2020, the patient experienced disease progression and was treated with daratumumab, bortezomib, and dexamethasone (Dara-Vd) for six cycles, followed by maintenance treatment with Dara-d achieving a very good partial response. In November 2020, the patient underwent HSCT from his HLA full-matched brother achieving SCR with no measurable residual disease (MRD). HSCT was complicated by the development of grade 2 acute GVHD of the lower gastrointestinal tract that responded to short-term steroid treatment, without any other relevant clinical issues. Unfortunately, in August 2022, free-light chain K reappeared in peripheral blood at a very low level. At this time, the patient was asymptomatic with normal performance status and no evidence of GVHD. He was kept under strict observation until November 2022, when MM re-evaluation documented a significant increase of free-light chain K, weak positivity of Bence-Jones K protein in urine, no anemia, no renal failure, and no hypercalcemia. Bone marrow aspirate did not show an excess of myeloma cells, but MRD evaluated by multicolor cytofluometry turned positive (sensibility 10−4). 18-FDG-PET/CT scan showed a low uptake at the posterior arch of the seventh left rib. Chimerism on T-cells was 100% full donor. Considering the previous patient's treatment history and the results of the MajesTEC-1 study in triple class exposed patients,4 which showed Te significantly longer PFS if compared with other available standard-of-care treatments1 including Pomalidomide or Carfilzomib-based combinations or Belantamab Mafodotin, our proposal fell on the use of Te through an Italian named patient program (NPP) at that time available. The patient became eligible for NPP, gave the formal consent, and the Local Ethics Committee approved the treatment. Table 1 summarizes patient's laboratory characteristics at baseline before starting Te therapy. Te dosing and pre-treatment medications (corticosteroid, anti-histamine, and anti-pyretic) were administered according to the Investigational Product Preparation Instructions (IPPI). Te first (60 mcg/kg), second (300 mcg/kg), and third (1500 mcg/kg) doses were administered sc at Days 1, 4, and 8 during hospitalization starting on December 6, 2022. Subsequent doses of 1500 mcg/kg were administered sc as an outpatient weekly from Week 2 up to Month +6, then every 14 days according to NPP IPPI; at present, treatment with Te is still ongoing. Laboratory evaluation showed a very rapid and deep reduction of K light chain in blood (from 289 to 0.66 mg/L) and urine (from 66 to 0 mg) after 4 weeks of treatment, respectively. In the following 6 months of treatment with Te all laboratory parameters of response were maintained (Table 1); bone marrow morphologic and cytofluometric evaluation (sensibility 10−4) performed at Week 24 did not show the presence of monoclonal plasma cells confirming the achievement of an MRD negative SCR (Table 1). 18-FDG-PET/CT could not be repeated because of the patient's refusal. Regarding side effects, the first three doses were complicated by Grade 1 CRS according to the American Society for Transplantation and Cellular Therapy criteria5 (chills and fever 24 h after each administration), which was easily controlled with paracetamol. All subsequent doses were administered as scheduled, except one (Week 10), which had a 1-week delay due to upper respiratory tract infection requiring antibiotics. Since Week 8 from Te start, because of the development of marked hypogammaglobulinemia (IgG 396 mg/dL), the patient started receiving monthly intravenous immunoglobulins (20 g). No other infectious, hematological, or extra-hematological complications or GVHD occurred during treatment with Te. This case report describes for the first time the positive effect of Te administration in a patient with MM in relapse 21 months after HSCT. Correlative analysis from MajesTEC-1 study indicated a relationship between higher baseline CD3 and CD8 T-cell counts and the response to Te.6 Our patient, in the period after HSCT, was treated with only a short-term steroid treatment for acute GVHD and did not receive any other anti-MM treatment. CD3- and CD8-positive lymphocyte counts before starting Te were rather high (1.9 × 109/L and 1.6 × 109/L, respectively) (Table 1). This condition may have facilitated the achievement of a new rapid SCR. Despite these high T-lymphocyte counts, there was no occurrence of high-grade CRS, ICANS, or GVHD reactivation. Thanks to the availability of new active agents and its high toxicity, HSCT is nowadays rarely performed in MM patients and is more and more reserved for selected young and fit patients.2 Because the risk of relapse after HSCT is still high, many patients eventually require further anti-MM therapy. Our single case supports the possible use of Te after HSCT; however, the efficacy and safety of this treatment should be confirmed in other patients. FZ reports consulting fees, honoraria and research funding from AbbVie, Amgen, Argenx, BeiGene, Grifols, Janssen, Novartis, Sobi, Gilead, Lilly, Takeda. Data available on request from the authors.